This study compared the effects of ad libitum (AL) overfeeding and moderate or marked dietary restriction (DR) on aged-related degenerative and proliferative changes of the endocrine pancreas in Sprague-Dawley (SD) rats. SD rats were fed Purina Certi ed Rodent Diet AL (group 1), DR at 72-79% of AL (group 2), DR at 68-72% of AL (group 3) or DR at 47-48% of AL (group 4) for 106 weeks. Interim necropsies were performed at 13, 26, and 53 weeks, after a 7-day 5-bromo-2-deoxyuridin e (BrdU)-lled minipump implantation. Before each necropsy, glucose and serum insulin levels were measured. In addition to the routine histopathologi c examination performed in both sexes, determination of 9 pancreatic islet stereologic parameters was done in males at 13, 26, and 53 weeks. In AL-fed rats, early changes in the islet morphology occurred, which resulted in a high incidence of islet brosis, focal hyperplasias and adenomas by two years. DR was dose-proportionall y associated with decreased glucose and serum insulin levels, and delayed the onset, and decreased the incidence and severity of islet brosis and hyperplasia. Results of the stereology supported the histopathologi c and clinical chemistry ndings. It demonstrated that, compared to AL-fed rats, DR-fed rats had smaller pancreas, smaller pancreatic islets, smaller insulin secreting cell volumes, a lower degree of islet brosis and a lower islet cell BrdU labeling index, which correlated with a lower incidence of islet adenoma and carcinoma at study termination. Moderate and marked degrees of DR delayed the onset and severity of islet hyperplasia and brosis in a temporal-and dose-related manner. In contrast to marked DR, which dramatically prevented these changes, moderate DR delayed but not prevented onset of islet tumors. These ndings support the concept that moderate DR results in a better-controlled animal model with a lower incidence or delayed onset of chronic spontaneou s endocrine diseases in the rat bioassay.